Oral administration of 6-hydroxy-oxymorphone for use as an analgesic

ABSTRACT

In a method of treating pain, a patient is administered a pharmaceutical composition of 6-hydroxy oxymorphone in amount sufficient to induce analgesia. In one embodiment, the pharmaceutical composition is administered orally. Any known or later developed method of oral delivery may be used. To achieve the desired analgesic effect, blood plasma levels of 6-hydroxy oxymorphone are raised to at least approximately 0.2 ng/mL. Most preferably blood plasma levels of 6-hydroxy oxymorphone range at least 0.3 ng/mL during treatment. Administration of compositions containing 6-hydroxy oxymorphone, and one or more carriers, diluents, and excipients in an amount sufficient to induce analgesia is also contemplated.

[0001] This application relates to provisional patent application serial Nos. 60/329,445 filed Oct. 15, 2001, .60/329,432 filed Oct. 15, 2001, 60/303,357 filed Jul. 6, 2001, and 60/329,444 filed Oct. 15, 2001.

BACKGROUND

[0002] 1. Field of Invention

[0003] The invention relates to methods for alleviating pain. More particularly, the invention relates to methods for alleviating pain by administering 6-hydroxy oxymorphone. Most particularly, the invention relates to methods of inducing analgesia by increasing blood plasma levels of 6-hydroxy oxymorphone through oral administration of a pharmaceutical composition containing 6-hydroxy oxymorphone.

[0004] 2. Summary of the Invention

[0005] The present invention provides methods of treating pain by administering a pharmaceutical composition comprising 6-hydroxy oxymorphone in an amount sufficient to induce analgesia. In one embodiment, the pharmaceutical composition is administered orally. Any known or later developed method of oral delivery may be used. To achieve the desired analgesic effect, blood plasma levels of 6-hydroxy oxymorphone are raised to at least about 0.2 ng/mL. Most preferably blood plasma levels of 6-hydroxy oxymorphone of at least about 0.3 ng/mL during treatment. Methods for administering compositions comprising 6-hydroxy oxymorphone, and one or more carriers, diluents, and excipients in an amount sufficient to induce analgesia are also provided.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006]FIG. 1 is a pharmacokinetic profile for 6-hydroxy oxymorphone with PID scores.

[0007]FIG. 2 is a pharmacokinetic profile for oxymorphone with PID scores.

[0008]FIG. 3 is a pharmacokinetic profile for 6-hydroxy oxymorphone with categorical pain scores.

[0009]FIG. 4 is a pharmacokinetic profile for oxymorphone with categorical pain scores.

DETAILED DESCRIPTION

[0010] The methods described herein provide for the administration of a pharmaceutical composition containing 6-hydroxy oxymorphone as an active ingredient. In a preferred embodiment the preferred composition comprises 6-hydroxy oxymorphone alone (excepting, of course, carriers, diluents, and other excipients). In other preferred embodiments, 6-hydroxy oxymorphone may be combined with other opioids or other pharmaceutical agents. For example, another preferred embodiment provides compositions comprising both 6-hydroxy oxymorphone and its parent, oxymorphone.

[0011] In two separate studies, blood plasma levels and indications of pain relief were recorded over a 12 hour period after. FIGS. 1-4 show graphical representation of the data combining the two studies such that the effect of blood plasma levels of oxymorphone and its metabolite, 6-hydroxy oxymorphone on pain can be evaluated.

[0012] The administration of oxymorphone yields blood plasma levels of oxymorphone and all of its metabolites, 6-hydroxy oxymorphone. Oxymorphone levels peak within 2 hours, fall slightly, and plateau. Interestingly, the level spikes again at 4-6 hours from administration. After this time, oxymorphone levels again drop and eventually fall to levels near the earlier plateau.

[0013] Like oxymorphone, 6-hydroxy oxymorphone blood plasma levels peak within 2 hours after administration. After the initial peak, however, a more or less steady decline in the 6-hydroxy oxymorphones plasma levels is observed.

[0014] Comparing these levels to the pain profiles, a correlation between the 6-hydroxy oxymorphone blood plasma levels and pain relief can be seen. The pain levels nearly mirror the 6-hydroxy oxymorphone levels, with substantial rises in relief near the spikes associated with 6-hydroxy oxymorphone blood levels. Thus, pain relief can be achieved through administration of 6-hydroxy oxymorphone alone.

[0015] In addition to the pharmacokinetic studies, binding studies have been conducted to compare the binding affinity of 6-hydroxy oxymorphone to that of oxymorphone. The results are reported in TABLE 1. These results clearly indicate that 6-hydroxy oxymorphone has great binding affinity for the δ, κ, and μ receptor cites, comparable to the binding affinity of its parent. The inventors believe that by virtue of this binding affinity, 6-hydroxy oxymorphone has similar analgesic effects to its parent, oxymorphone. TABLE 1 ASSAY REPORT 6-HYDROXY OXYMORPHONE OXYMORPHONE 10 nm 10 μm 10 nm 10 μm 1.0 E−8 1.0 E−5 1.0 E−8 1.0 E−5 Opiate, Delta 1 −4.12% 90.48% −18.26%  89.03% Opiate, Delta 2   7.19% 55.45%   7.76%  72.74% (Human Recombinant) Opiate, Kappa   2.45% 62.47%   10.35%  89.41% (Human Recombinant Opiate, Mu   63.16%  99.91%   85.42% 100.39% (Human Recombinant)

[0016] Accordingly, methods of administering the metabolite, 6-hydroxy oxymorphone, directly have been developed. It is believed that the β isomer has greater efficacy in the treatment of pain, but this disclosure is not limited to use of that isomer alone. Pharmaceutical compositions containing either 6-α-hydroxy oxymorphone, 6-β-hydroxy oxymorphone, or mixtures thereof can be used in the invention.

[0017] Formulation as a suspension, syrup, or other liquid, tablet, capsule, liquid-filled gel cap, or other solid or semi-solid means may be used. The composition may alternately be in the form of a time release formulation, including timed, suspended and extended release formulations. Regardless of the formulation, an amount of 6-hydroxy oxymorphone sufficient to induce analgesia will be supplied to the patient. Blood plasma levels of 6-hydroxy oxymorphone must be raised to levels sufficient to induce the desired level of analgesia.

[0018] The amount administered will be dependent upon normal criteria such as patient weight, intensity of pain, and other factors. Based on the pharmacokinetic studies, blood plasma levels around at least 0.2 ng/mL will provide some analgesia. The upper plasma level limit will be ultimately established by safety concerns. Over-dosing of any opioid, including 6-hydroxy oxymorphone, may lead to respiratory failure and other undesirable side effects and can even result in death. Preferably, the blood plasma level of 6-hydroxy oxymorphone will be raised to at least 0.3 ng/mL. Subsequent doses may be required to maintain these blood levels.

[0019] The preferred administration is of 6-hydroxy oxymorphone with appropriate carriers and excipients as will be readily apparent to those skilled in the art. The resulting blood plasma in these preferred administrations will therefore be substantially free of oxymorphone.

[0020] The above description encompasses some preferred embodiments of the invention. The disclosure is merely illustrative in nature and is not intended to limit the following claims. 

What is claimed is:
 1. A method of treating pain comprising the step of: administering to a patient a pharmaceutical composition comprising 6-hydroxy oxymorphone in an amount sufficient to induce analgesia.
 2. The method of claim 1 wherein said pharmaceutical composition is administered orally.
 3. The method of claim 2 wherein said pharmaceutical composition is administered in a form selected from a liquid formulation, syrup, suspension, solid formulation, tablet, capsule, liquid-filled gel cap, and a semi-solid formulation.
 4. The method of claim 1 wherein said administration is sufficient to raise blood plasma levels of 6-hydroxy oxymorphone to at least about 0.2 ng/mL.
 5. The method of claim 1 wherein said administration is sufficient to raise blood plasma levels of 6-hydroxy oxymorphone to at least about 0.3 ng/mL.
 6. A method of treating pain comprising the step of: orally administering to a patient a pharmaceutical composition comprising 6-hydroxy oxymorphone, and one or more carriers, diluents, and excipients in an amount sufficient to induce analgesia.
 7. A method of treating pain comprising the step of: orally administering to a patient a pharmaceutical composition comprising 6-hydroxy oxymorphone and oxymorphone in an amount sufficient to induce analgesia.
 8. A pharmaceutical composition comprising 6-hydroxy oxymorphone in a formulation for oral delivery to animals including hormone. 